Opioids represent one of the most powerful treatments available for most forms of pain. However, negative health consequences, such as intoxication and physical dependence are a growing problem, and may result in opioid abuse and addiction. The prevalence, and how to prevent, reduce, and treat these negative health consequences of opioid administration in the context of pain are not well understood. Furthermore, the fear of opiate abuse and addiction by patients with pain has led to under- medication of patients with chronic pain. Discovery of DNA markers that may flag pain patients who are at increased risk for addiction to opioids may substantially improve clinical practice by more careful use of opiates in those who are susceptible and more aggressive use of opiates in those who really need them. We propose to identify genetic variants that confer significant risk for addiction to opiates when initially prescribed for pain control. We will use ultra-high throughput SNP marker genotyping platforms in a direct genome-wide search for susceptibility variants. In Phase I we propose to genotype 800 individuals addicted to opiates using Tag-SNP arrays with 317,000 markers and search genome-wide for association to opiate addiction. In parallel, we will carry out a linkage study within extended families that have at least 2 patients addicted to opiates. The top 1% SNPs (3000 SNPs) that show at least nominal significance will be selected for follow-up genotyping. The stringency of criteria for markers under linkage peaks will be less than that for markers outside of linkage peak such that up to half of the SNPs selected will be within linkage peaks and the remaining outside. In phase II these selected SNPs will be genotyped on other Caucasian samples of opiate addiction from the US, Europe and Australia cohort collections already funded by NIDA which total at least 800 cases and 800 controls. A joint analysis of genotypes of these 3000 SNPs in both cohorts will be performed, looking for association to opiate addiction. P-values will be corrected for 317,000 tests and SNPs that meet genome-wide significance after correction will be used to genotype addicted versus non- addicted patients in a prospective Icelandic cohort of individuals treated by prescription opioids for pain to confirm their utility in defining risk of addiction. The isolation of opiate addiction genes facilitates the study of their contribution to the risk of developing addiction following the use of prescription opioids, as the presence of at-risk or protective variants of opiate addiction genes might be used to predict the risk of becoming addicted to prescription opiates. Genes identified in this project may uncover biochemical pathways involved in addiction and possibly provide novel targets for the development of diagnostics and drug therapies.